1. Field of the Invention
This invention pertains to naturally-occurring insulin mediators, and in particular, two purified insulin mediators obtained from liver tissue. Additionally, a process for purification of the naturally-occurring substances is provided, together with a screening test for the detection of the diabetic state. Related artificial compounds can be similarly prepared
2. Background of the Prior Art
Numerous researchers have established that insulin, a major anabolic hormone, which plays a central role in the control of metabolism of carbohydrates, fats and proteins, acts indirectly, through the activity of a plurality of insulin mediators, that apparently link the hormone, and a variety of regulating enzymes. Thus, Larner, Diabetes, 21, page 428 (1972) suggested the existence of an insulin mediator blocking the activation of cyclic AMP-dependent protein kinase Subsequently, Jarett et al, Science 206, pages 1407-1408 (1979) confirmed the activation, by the proposed mediators, of PDH in adipocyte mitochondria. Subsequently, Mato et al, Journal of Biological Chemistry 262, pages 2131-2137 (1987), and Saltiel et al, Proceedings of the National Academy of Science 83, pages 5793-5797 (1986) have identified insulin "modulators", similar to glycosyl-phosphoinositol linkers known to anchor proteins to the external surface of cell membranes.
Thus, substantial evidence has been provided that there exists a plurality of insulin mediators which operate in conjunction with specific enzymes, in the multiple functions of insulin. There are at least suggestions that one or more of these mediators is derived from traditional glycosyl-phosphoinositol linkers, similar to known anchor proteins.
Effective identification and treatment of the diabetic state, and other functions controlled or impacted by insulin, may be most effectively carried out through the mechanism of insulin mediators. U.S. Pat. No. 4,446,064, Larner et al, discloses a partial purification process for the isolation of an insulin mediator substance derived from muscle tissue, the isolated fraction having the ability to inhibit protein kinase However, the purification system provided therein is incomplete, and the structure of the mediator collected in the obtained fraction is not identified. Effective in vivo treatment of diabetes, and related insulin conditions, as well as the use of the mediators as diagnostics, requires high degrees of purification of mediator substances. Additionally, production of large amounts of the mediator substance, preferably through synthetic or biological means, requires identification of structure information concerning these mediators.
Accordingly, it remains an objective of the art to provide a highly purified insulin mediator, a system for purification of the same, and the structure of the insulin mediator, for the more effective treatment of insulin-resistant conditions.